Surrogate End Points for Overall Survival in Neoadjuvant Randomized Clinical Trials for Early Breast Cancer
Journal of Clinical Oncology, vol. 43, pp. 1441–1452
Abstract
PURPOSE To assess trial-level surrogacy value for overall survival (OS) of the pathologic complete response (pCR) and invasive disease-free survival (iDFS) in randomized clinical trials (RCTs) for early breast cancer (BC). METHODS Individual patient data of neoadjuvant RCTs with available data on pCR, iDFS, and OS were included in the analysis. We used the coefficient of determination R 2 from weighted linear regression models to quantify the association between treatment effects on OS and on the surrogate end points. RESULTS Eleven RCTs, for a total of 15 treatment comparisons and 12,247 patients, were included in the analysis. There was a weak association between hazard ratios (HRs) for OS and odds ratio of pCR overall ( R 2 , 0.07; 95% CI, 0.00 to 0.48), as well as in all the subgroups explored. Overall, the R 2 for the association between HR OS and HR iDFS was 0.46 (95% CI, 0.08 to 0.71), which is just below the cutoff of 0.5 for moderate surrogacy. In the majority of subgroups explored, the R 2 ranged from 0.5 to <0.7, while in hormone receptor–/human epidermal growth factor receptor 2– subtype, histologic grade 1-2 tumors, and lobular tumors, surrogacy was strong (ie, R 2 ≥0.7). The surrogacy value of iDFS for OS was affected by follow-up (FUP) length: R 2 substantially increased up to 36 months of FUP, with little further improvement after 48 months of FUP. CONCLUSION iDFS with sufficient FUP is an acceptable surrogate end point to confidently anticipate final OS results of neoadjuvant RCTs for early BC. This recommendation holds true across many subgroups, with the notable exception of HR+ disease. There is definite need to reassess whether OS is the optimal end point for treatment efficacy measurement in HR+ early BC.
Authors 31
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Humanitas University · Humanitas Gavazzeni
Affiliation as printed
Humanitas University, Rozzano, Italy
Medical Oncology Unit, Humanitas Gavazzeni, Bergamo, Italy
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Affiliation as printed
German Breast Group, Neu-Isenburg, Germany
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Affiliation as printed
Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
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Affiliation as printed
Department of Economics, Management and Statistics, University of Milano-Bicocca, Milan, Italy
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Affiliation as printed
University Hospital Frankfurt, Frankfurt, Germany
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Helios Hospital Berlin-Buch · Helios Kliniken
Affiliation as printed
Helios Kliniken, Berlin-Buch, Germany
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Philipps University of Marburg · Universitätsklinikum Gießen und Marburg
Affiliation as printed
Institute of Pathology, Philipps-University Marburg, University Hospital UKGM Marburg, Marburg, Germany
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Affiliation as printed
Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
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Humanitas University · Humanitas Gavazzeni
Affiliation as printed
Humanitas University, Rozzano, Italy
Medical Oncology Unit, Humanitas Gavazzeni, Bergamo, Italy
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Affiliation as printed
Universitätsklinikum Erlangen, Erlangen, Germany
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German Cancer Research Center · National Center for Tumor Diseases
Affiliation as printed
National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany
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Affiliation as printed
Gynäkologisch-onkologische Praxis Neumarkt, Neumarkt in der Oberpfalz, Germany
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Affiliation as printed
Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
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Affiliation as printed
Medical Oncology Unit, Humanitas Gavazzeni, Bergamo, Italy
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University Hospital Schleswig-Holstein
Affiliation as printed
Universitätsklinikum Schleswig-Holstein, Klinik für Gynäkologie und Geburtshilfe, Schleswig-Holstein, Germany
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Affiliation as printed
Departement Interdisziplinäre medizinische Dienste, Kantonsspital St Gallen, Brustzentrum, St Gallen, Switzerland
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Technische Universität Dresden
Affiliation as printed
Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany
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Affiliation as printed
Klinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Frankfurt, Frankfurt, Germany
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Charité - Universitätsmedizin Berlin · Kliniken Essen-Mitte
Affiliation as printed
Department of Gynecology with Breast Center, Evang. Kliniken Essen-Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany
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Heidelberg University · Medizinische Fakultät Mannheim
Affiliation as printed
Medizinische Fakultät Mannheim, Universität Heidelberg, Universitätsfrauenklinik Mannheim, Mannheim, Germany
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Witten/Herdecke University · Helios Universitätsklinikum Wuppertal
Affiliation as printed
Breast Unit, University Hospital Helios, University Witten Herdecke, Wuppertal, Germany
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Affiliation as printed
Mammazentrum Hamburg, Hamburg, Germany
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University of Tübingen · Arbeitsgemeinschaft Gynäkologische Onkologie Studiengruppe
Affiliation as printed
AGO Study Group and University Hospital Tübingen, Tübingen, Germany
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Affiliation as printed
Klinik für Gynäkologie und Geburtsmedizin, Uniklinik Aachen, Aachen, Germany
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Affiliation as printed
Rotkreuzklinikum Munich, Munich, Germany
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Charité - Universitätsmedizin Berlin
Affiliation as printed
Gynakologie mit Brustzentrum, Charité Universitätsmedizin Berlin, Berlin, Germany
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Düsseldorf University Hospital
Affiliation as printed
Universitätsklinik Düsseldorf, Düsseldorf, Germany
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Affiliation as printed
Center for Familial Breast and Ovarian Cancer, University of Cologne, Cologne, Germany
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Affiliation as printed
German Breast Group, Neu-Isenburg, Germany
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Harvard University · Dana-Farber Cancer Institute · Frontier Science & Technology Research Foundation, Inc. · Dana-Farber/Harvard Cancer Center
Affiliation as printed
Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Harvard T.H. Chan School of Public Health, and Frontier Science & Technology Research Foundation, Boston, MA
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Affiliation as printed
German Breast Group, Neu-Isenburg, Germany
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References 55
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